Rectal Administration Of Indomethacin Research Articles

The risk of post-ERCP pancreatitis and the protective effect of rectal indomethacin in cases of attempted but unsuccessful prophylactic pancreatic stent placement

It is believed, based on limited observational data, that an unsuccessful attempt to place a prophylactic pancreatic stent substantially increases the risk of post-ERCP pancreatitis (PEP). To better understand the risk of PEP in patients with failed pancreatic stent placement (FPS) and the impact of rectal indomethacin on this risk. Secondary analysis of randomized, controlled trial data. University of Michigan and Indiana University. A total of 577 clinical trial participants at elevated risk for PEP. Pancreatic stent placement. Within the placebo group, we compared PEP rates in patients with FPS, patients who underwent successful stent placement, and in those without a stent attempt. We also performed a regression analysis evaluating the association between FPS and PEP. To define the protective effect of indomethacin, we repeated these analyses in the indomethacin group and in the full study cohort. The incidence of PEP among patients in the placebo group who experienced FPS was 34.7%, significantly exceeding rates in patients who underwent successful stent placement (16.4%) and in those without a stent attempt (12.1%). After we adjusted for known PEP risk factors, FPS was found to be independently associated with PEP. Among the indomethacin group and in the full cohort, FPS was not associated with a higher risk of PEP. Low event rate, FPS not prospectively captured. FPS appears to confer an increased risk of PEP, which is attenuated by rectal indomethacin administration. These findings highlight the importance of adequate training and proficiency before endoscopists attempt pancreatic stent placement and the routine use of rectal indomethacin in high-risk ERCP cases.

Does Rectal Indomethacin Eliminate the Need for Prophylactic Pancreatic Stent Placement in Patients Undergoing High-Risk ERCP? Post hoc Efficacy and Cost-Benefit Analyses Using Prospective Clinical Trial Data

A recent large-scale randomized controlled trial (RCT) demonstrated that rectal indomethacin administration is effective in addition to pancreatic stent placement (PSP) for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. We performed a post hoc analysis of this RCT to explore whether rectal indomethacin can replace PSP in the prevention of PEP and to estimate the potential cost savings of such an approach. We retrospectively classified RCT subjects into four prevention groups: (1) no prophylaxis, (2) PSP alone, (3) rectal indomethacin alone, and (4) the combination of PSP and indomethacin. Multivariable logistic regression was used to adjust for imbalances in the prevalence of risk factors for PEP between the groups. Based on these adjusted PEP rates, we conducted an economic analysis comparing the costs associated with PEP prevention strategies employing rectal indomethacin alone, PSP alone, or the combination of both. After adjusting for risk using two different logistic regression models, rectal indomethacin alone appeared to be more effective for preventing PEP than no prophylaxis, PSP alone, and the combination of indomethacin and PSP. Economic analysis revealed that indomethacin alone was a cost-saving strategy in 96% of Monte Carlo trials. A prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP. This hypothesis-generating study suggests that prophylactic rectal indomethacin could replace PSP in patients undergoing high-risk ERCP, potentially improving clinical outcomes and reducing healthcare costs. A RCT comparing rectal indomethacin alone vs. indomethacin plus PSP is needed.

Can rectal NSAIDs prevent post-ERCP pancreatitis?

Acute pancreatitis is the most common and feared complication following endoscopic retrograde cholangiopancreatography (ERCP). Pharmacological prevention of post-ERCP pancreatitis has been disappointing, especially in high-risk patients. However, a prospective multicentre trial has demonstrated the efficacy of rectal administration of indomethacin for preventing post-ERCP pancreatitis in high-risk cases.

Post-endoscopic retrograde cholangio-pancreatography pancreatitis: Is time for a new preventive approach?

Acute pancreatitis is the most common serious complication of endoscopic retrograde cholangio-pancreatography (ERCP) and its incidence may exceed 25% in some high-risk patient subsets. In some patients, pancreatitis may follow a severe course with pancreatic necrosis, multiorgan failure, permanent disability and even death. Hence, approaches which minimize both the incidence and severity of post-ERCP pancreatitis are worth pursuing. Pancreatic stents have been used with some success in the prevention of post-ERCP, while so far pharmacological trials have yielded disappointing results. A recent multicenter, randomized, placebo-controlled, double-blind trial has shown that rectally administered indomethacin is effective in reducing the incidence of post-ERCP pancreatitis, the occurrence of episodes of moderate-to-severe pancreatitis and the length of hospital stay in high-risk patients. These results together with the demonstration that rectal administration of indomethacin is not associated with enhanced risk of bleeding strongly support the use of this drug in the prophylaxis of post-ERCP pancreatitis.

Effect of Preoperative Rectal Indomethacin on Postoperative Pain Reduction After Open Cholecystectomy

The preoperative administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to have a positive impact on postoperative pain, but there is little research regarding the use of rectal NSAIDs given before surgery. The purpose of this study was to evaluate the effects of rectally administered indomethacin on postoperative pain in patients undergoing open cholecystectomy. A randomized controlled design was used to compare rectally administered indomethacin with placebo. Pain intensity, total opioid dose, and postoperative time to first request for analgesic were evaluated. The indomethacin group experienced significantly less postoperative pain and required less total opioid dose compared with the placebo group. Preoperative rectal administration of indomethacin reduces postoperative pain in open cholecystectomy when compared with placebo.

Effect of preoperative rectal indomethacin on postoperative pain reduction after open appendectomy

One of the major challenges faced by the treatment planning teams is how to manage postoperative pain. Previous studies agreed upon the effects of preoperative administration of nonsteroidal anti-inflammatory drugs on postoperative pain, but all have focused on patients with surgical noninflammatory diseases (ie, inguinal hernia or breast biopsy). The aim of this study was to evaluate the effects of rectal indomethacin on reducing postoperative pain in patients with acute appendicitis. It is a simple randomized, clinical trial including 200 patients with acute appendicitis who were divided into two groups (A1 and A2). The case group (A1) received 100 mg rectal indomethacin during 2 hours before the operation. Pain intensity was assessed in all patients using a visual analog scale (VAS). Similarly, total dosage of meperidine analgesic medication and postoperative time to use of rescue analgesia were evaluated. Patients who received preoperative rectal indomethacin (A1) showed a significant reduction in the VAS score. Also, a reduction in total dose of meperidine and longer time to use of rescue analgesic medication were observed in A1 group. Preoperative administration of rectal indomethacin in acute appendicitis reduces postoperative pain.

A scanning electron microscopic study of the morphological changes in rat small intestinal mucosa treated by intracolonic indomethacin

Rectal administration of indomethacin induces longitudinal ulcers in the rat small intestine. The current study investigated a sequence of progressive villus injury in this enteropathy, especially by the use of scanning electron microscopy. The initial change was the distortion of several villi on the mesenteric side in the mid-small intestine identified at 0.5 h, even though there was no obvious change under light microscope or dissecting microscope at this time. During the subsequent 2h, distortion of the villi was accompanied by several epithelial defects, and epithelial detachment occurred on the villi tips. Extension of epithelial defects and exposure of the villus core progressed during subsequent periods. The injured villi were confluent with each other on the mesenteric side throughout the 12h after dosing. These findings suggest that the initial mucosal injury induced by the rectal route of administration was not extensive; rather, several villi were focally damaged on the mesenteric side in the mid-small intestine, eventually resulting in a longitudinal ulcer. Although the overall progression after indomethacin administration by the rectal route was similar to that occurrmg after subcutaneous administration, villus change seems to occur much earlier after rectal dosage.

Effect of indomethacin suppositories on rectal polyposis in patients with familial adenomatous polyposis

Oral sulindac is known to reduce polyps in patients with familial adenomatous polyposis (FAP). The authors speculated that rectal administration of indomethacin would be effective therapy for adenomas in the rectal remnant of FAP. Eight patients with FAP who had been treated by total colectomy with ileorectal anastomosis were administered an indomethacin suppository (50 mg) once or twice daily during a period of 4 or 8 weeks. The number of polyps at the same site within the rectum was counted under proctoscopy prior to, at the end of, and after the treatment. In four patients, proliferative activity of the rectal mucosa was assessed by immunohistochemical staining for MIB-1. In six of the eight patients who initially had ten or more polyps, the number of polyps decreased to fewer than five, whereas such a decrease could not be observed in the remaining two patients. In the six patients, the number of polyps increased after indomethacin was discontinued. The proliferative activity of the rectal mucosa was higher at the end of treatment than it was prior to indomethacin administration. Indomethacin suppositories may be effective in the management of rectal adenomatosis in patients with FAP.

Disposition and protective effect against irritation after intravenous and rectal administration of indomethacin loaded nanocapsules to rabbits

Indomethacin loaded poly(D,L-lactide) nanocapsules (PLA-NCs) were investigated after intravenous and rectal administration to rabbits. A rebound of indomethacin plasma concentrations attributed to enterohepatic circulation of indomethacin was observed with all preparations. Following i.v. infusions, results showed that PLA-NCs altered the pharmacokinetics of indomethacin in ways that accelerate the extravascular distribution by enhancing the capture of the colloidal carrier by the liver and, at the same time, modifying the elimination rate of indomethacin. After rectal administration of indomethacin formulations, drug plasma concentration profiles revealed that absorption was more complete and more progressive with nanocapsules than with solution. T max had nearly the same value for all formulations, and bioavailability of indomethacin by this route was increased by nanoencapsulation. The terminal half-life of indomethacin was significantly lower when the drug was given by the rectal route either in solution by PLA-NCs, as compared to suppository. PLA-NCs exhibited a protective effect against the rectal irritability of indomethacin which can be attributed to the reduction of direct contact of free indomethacin with rectal mucosa.

Thermally gelling poloxamine Synperonic T908 solution as a vehicle for rectal drug delivery.

Thermally reversible gels of the block copolymer, Synperonic T908, have been evaluated as vehicles for the rectal administration of indomethacin. Prolonged plasma levels of indomethacin following rectal administration in such gels was observed with the 40% w/w Synperonic T908 gels when compared with commercial suppositories. The release rate decreased with an increase in gel concentration over the range 30% to 40% w/w. Histological observation showed no damage to the rectal mucosal membrane in animals at 6 h after the administration of a 40% w/w gel.

Investigation on rectal absorption of indomethacin from sustained-release hydrogel suppositories prepared with water-soluble dietary fibers, xanthan gum and locust bean gum.

Sustained-release hydrogel suppositories prepared with water-soluble dietary fibers, xanthan gum and locust bean gum, were evaluated as a vehicle for rectal administration of indomethacin (IMC) in rabbits. The drug plasma levels were compared with those after rectal administration of commercial suppositories. When the commercial suppositories were given to rabbits, the plasma concentration reached the maximum level at 30 min after administration followed by a quick reduction, while no sharp peak of plasma levels was seen with the hydrogel suppositories. In particular, the plasma levels observed with the hydrogel suppositories of 1% (w/v) gum concentration were sustained much longer than those after dosing with the commercial suppositories; the mean residence times had higher values without a decrease in the area under the plasma concentration vs. time curves. Histopathological study showed good biological safety of the hydrogel suppositories to the rectal mucosa. These results suggested that the IMC hydrogel suppositories prepared with xanthan gum and locust bean gum were a practical rectal preparation with prolonged action and reduced side effects.

Treatment of Ureteric Colic. Intravenous versus Rectal Administration of Indomethacin

A randomised multicentre clinical trial was undertaken to compare the effect on pain of indomethacin administered either intravenously or rectally to 116 patients with ureteric colic. Adverse reactions were also assessed. Of the patients receiving the intravenous injection, 48/53 (91%) achieved good pain relief (i.e. no supplementary analgesia was required) 30 min after administration, compared with 46/63 (73%) receiving the enema. Significantly more side effects occurred in the group treated intravenously. It was concluded that indomethacin administered as an enema was less effective than the intravenous form, but it should be regarded as a good alternative in the treatment of ureteric colic.

Evaluation of polyvinyl alcohol hydrogel as a sustained-release vehicle for rectal administration of indomethacin.

In order to evaluate an indomethacin polyvinyl alcohol (PVA) hydrogel for rectal administration, the in vitro release characteristics of indomethacin from the hydrogel and indomethacin plasma concentrations after rectal administration were examined. The PVA hydrogel containing indomethacin was prepared by a low-temperature crystallization method. The release of indomethacin from the PVA hydrogel agreed with the Fickian diffusion model for 10 hr. Rectal administration of indomethacin hydrogels to rats yielded high indomethacin plasma concentrations, without producing a sharp peak, and a sustained-release effect. In dogs, the indomethacin hydrogel produced a similar sustained-release effect; however, the indomethacin plasma concentration was relatively low compared with that of an indomethacin suppository.

Effect of Pluronic gels on the rectal absorption of indomethacin in rabbits.

Indomethacin gel preparations made by dissolving the drug in Pluronic aqueous gels were administered rectally to rabbits and the drug plasma levels were determined. When indomethacin gel preparations with 20% (w/w) Pluronic F-127 were given to rabbits, the plasma concentration reached the maximum level 0.5 h after administration. On the other hand, the 25% (w/w) Pluronic F-127 gel preparation did not show a sharp peak of plasma concentration and produced a sustained-release effect. The 30% (w/w) gel preparation also gave a sustained-release effect, but it was not a desirable preparation because its [AUC] 100 was only half that of a commercial suppository. Pluronic F-108 and Pluronic F-98 did not give a sustained-release effect at the concentration of 25% (w/w).Damage to the mucosal membrane by Pluronic F-127 was rarely found in the rectum. In addition, the individual differences in drug plasma levels following rectal administration of the 25% (w/w) Pluropic F-127 gel preparation were small compared with those of other preparations.These results suggest that the 25% (w/w) Pluronic F-127 gel is most suitable for use as a vehicle for rectal administration of indomethacin with prolonged action and with reduced side effects.

Pluronic F-127 gels as a novel vehicle for rectal administration of indomethacin.

Pluronic F-127 gels as a novel vehicle for rectal administration of indomethacin.

The effect of indomethacin on plasma levels of prostaglandin F2alpha in women in labour.

Prostaglandin F2alpha was measured by means of radiommunoassay in the serum of women in the active phase of term labour before and after rectal indomethacin administration. Samples of blood were collected every 20 or 30 seconds, between and during contractions. There was a significant decrease of the level of PGF2alpha in plasma 30 to 30 minutes after indomethacin administration, but the pattern of rapid short-term fluctuations in prostaglandin levels was unaltered.